The strategy to support virological suppression on second-line antiretroviral treatment (ART) includes the provision of ART that has a low pill burden, good tolerability, low toxicity, is easily monitored, has a high barrier to resistance, and that is low cost. The fixed-dose combination of tenofovir-lamivudine-dolutegravir offers significant advantage as a potential second-line regimen compared to the World Health Organization standard of care second-line regimen of zidovudine-lamivudine-dolutegravir, in terms of cost, tolerability and monitoring requirements. The ARTIST study is a phase 2, randomised, double-blind, placebo-controlled trial aiming to determine the proportion of patients achieving virological suppression when recycling the tenofovir-emtricitabine/lamivudine backbone with dolutegravir (tenofovir-lamivudine-dolutegravir fixed-dose combination) as a second-line with and without a lead-in supplementary dose of dolutegravir, in patients failing a tenofovir-emtricitabine/lamivudine-efavirenz first-line regimen. There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. The strategy of giving a lead-in supplementary dose of dolutegravir is in view of the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks after efavirenz is stopped; the inducing effect decreases with time after efavirenz is stopped. Given that these patients will have elevated viral loads, a high baseline risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance and efavirenz resistance, and the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks, this study will comprise two stages. The first stage will evaluate virological suppression in 62 participants initiated on the fixed-dose combination of tenofovir-lamivudine-dolutegravir with a lead-in supplementary dose of dolutegravir for the first 14 days. The study will progress to the second stage if this strategy proves effective, and 130 participants will then be randomised to receive the fixed-dose combination of tenofovir-lamivudine-dolutegravir with and without this lead-in dose. The primary endpoint is virological suppression (viral load <50 copies/mL) at 24 weeks. A pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and 24 participants in stage 2, to assess the trough concentrations of dolutegravir and off-treatment concentrations of efavirenz at day 3, 7, 14, and 28. This is to evaluate the need for the lead-in supplementary dose of dolutegravir.
Name: Dolutegravir 50 mg
Name: Placebo
Description: Proportion of participants with HIV viral load <50 copies/mL at 24 weeks analysed by modified intention to treat (ITT) and according to the FDA snapshot algorithm, overall and stratified by the presence or absence of resistance to tenofovir and lamivudine at baseline.
Measure: Virological suppression at 24 weeks Time: 24 weeksDescription: To describe resistance profile at baseline (NRTI and efavirenz resistance), and treatment-emergent resistance to integrase inhibitor and NRTI in participants who experience virological failure.
Measure: Antiretroviral resistance mutations by genotypic resistance testing Time: Baseline, 24 and 48 weeksDescription: To evaluate the trough concentrations (ng/mL) of dolutegravir and the residual concentrations (ng/mL) of efavirenz in the period after switching regimens. To evaluate the proportion of participants with dolutegravir trough concentrations above the protein-adjusted 90% inhibitory concentration (PA-IC90) value at all pharmacokinetics time points.
Measure: Residual efavirenz concentrations and dolutegravir trough concentrations Time: First 28 daysDescription: Proportion of participants with HIV viral load <50 copies/mL at 12 and 48 weeks analysed by modified ITT.
Measure: Virological suppression at 12 and 48 weeks (modified ITT) Time: 12 and 48 weeksDescription: Proportion of participants with HIV viral load <50 copies/mL at 12, 24 and 48 weeks analysed per protocol.
Measure: Virological suppression at 12, 24 and 48 weeks (per protocol) Time: 12, 24 and 48 weeksDescription: To describe tenofovir-diphosphate concentration (ng/mL) in participants who experience virological failure and matched controls from among those who are suppressed at 24 and 48 weeks.
Measure: Adherence to treatment Time: 24 and 48 weeksDescription: Change in CD4 count from screening at week 24 and 48.
Measure: CD4 change at 24 and 48 weeks Time: 24 and 48 weeksDescription: To describe grade 3 and 4 drug-related adverse events, serious adverse events, and any adverse event requiring discontinuation of any drug in the ART regimen.
Measure: Adverse events Time: 48 weeksDescription: To describe all-cause mortality.
Measure: All-cause mortality Time: 48 weeksAllocation: Randomized
Parallel Assignment
There are 2 SNPs
There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. --- K65R ---
There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. --- K65R --- --- M184V ---